I.M. Larina – 

Dr Sc. (Med.), Professor, Chief of Proteomics laboratory, Russian Federation State Scientific Center Institute for

Biomedical Problems of RAS (Moscow)

E-mail: irina.larina@gmail.com A.I. Grigoriev – 

Academician of RAS, Dr. Sc. (Med.), Scientific Director of Russian Federation State scientific center Institute for Biomedical Problems of RAS (Moscow) E-mail: grigoriev@imbp.ru 

Оxidative stress – a potentially important secondary link in the etiopathogenesis of most dysfunctions and multiorgan disorders caused by CP in humans and experimental animals The aim of the study was to determine the presence and biological role of protein-markers of oxidative stress in the body fluids of astronauts who have completed long space flights on the ISS. Proteome analysis has identified changes associated with CP factors, levels of regulatory proteins, including participants in coagulation cascades (F5, F13A1, F13B, etc.) and innate immune system proteins (C3, CFB, SPP1, C4A, ORM1, ORM2, CD14). Studies of proteomics based on chromato-masspectrometry, biological fluids of cosmonauts after six-year space flights clearly indicate the presence of oxidative stress, as a consequence of the effects on the body of the complex adverse factors. Panoramic, semi-quantitative and quantitative methods of proteomics based on masstrorometry for the study of blood and urine reveal the proteins participating in the pro- and antioxidant system, and the direction of changes in their concentrations shows the severity oxidative stress. The findings substantiate a new approach to finding the means and methods of preventing the adverse effects of spaceflight on humans: by preventing and ceding progressive damage to cellular and tissue structures. The aim of finding the means and methods to counteract the development of oxidative stress should become the most important scientific and practical task of gravitational physiology and medicine in the stage of preparation for ultra-long-range space flights. 

1. Grigoriev A.I., Egorov A.D. General mechanisms of the effect of weightlessness on the human body // Adv. Space Biol. Med. Review. 1992. V. 2. P. 1–42.
2. Kosmicheskaya biologiya i medicina. Sovmestnoe Rossijsko-amerikanskoe izdanie. M. 2009. T. 1–5. 758 s.
3. Goodwin Thomas J., Melpo Christofidou-Solomidou. Oxidative Stress and Space Biology: An Organ-Based Approach // Int. J. Mol. Sci. 2018. Apr. № 19(4). P. 959. 
4. Thirsk R., Kuipers A., Mukai C., Williams D. The space-flight environment: The International Space Station and beyond // CMAJ Can. Med. Assoc. J. 2009. V. 180. P. 1216–1220.
5. Kohen R., Nyska A. Oxidation of biological systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification // Toxicol. Pathol. 2002. V. 30. P. 620–650.
6. Höhn A., Weber D., Jung T., Ott C., Hugo M., Kochlik B., Kehm R., König J., Grune T., Castro J.P. Happily (n)ever after: Aging in the context of oxidative stress, proteostasis loss and cellular senescence // Redox Biol. 2017. V. 11. P. 482–501.
7. Alwood J.S., Tran L.H., Schreurs A.S., Shirazi-Fard Y., Kumar A., Hilton D., Tahimic C.G.T., Globus R.K. Dose- and Ion-Dependent Effects in the Oxidative Stress Response to Space-Like Radiation Exposure in the Skeletal System // Int. J. Mol. Sci. 2017. P. 18. P. 2117.
8. Tian Y., Ma X., Yang C., Su P., Yin C., Qian A.-R. The Impact of Oxidative Stress on the Bone System in Response to the Space Special Environment // Int. J. Mol. Sci. 2017. V. 18. P. 2132. 
9. Takahashi K., Okumura H., Guo R., Naruse K. Effect of Oxidative Stress on Cardiovascular System in Response to Gravity // Int. J. Mol. Sci. 2017. V. 18. P. 1426. 
10. Burns J., Manda G. Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance // Int. J. Mol. Sci. 2017. V. 18. P. 2755. 
11. Garrett-Bakelman et al. The NASA twins study: a multidimensional analysis of a year-long human spaceflight // Science. 2019. V. 364. P. 144.
12. Pastushkova L.K., Valeeva O.A., Kononikhin A.S., Nikolaev E.N., Larina I.M., Dobrokhotov I.V., Popov I.A., Pochuev V.I., Kireev K.S., Grigoriev A.I. Changes in Urine Protein Composition in Human Organism During Long Term Space Flights // Acta Astronautica. December 2012. V. 81.  № 2. P. 430–434.
13. Pastushkova L. Kh., Kashirina D.N., Kononikhin A.S., Brzhozovsky A.G., Ivanisenko V.A., Tiys E.S., Novosyolova N.M., Custaud M.-A., Nikolaev E.N., Larina I.M. The Effect of Long-term Space Flights on Human Urine Proteins Functionally Related to Endothelium // Human Physiology. 2018. V. 44. № 1. P. 85–92.
14. Brzhozovskiy A., Kononikhin A., Indeykina M., Pastushkova L., Popov I.A., Nikolaev E.N., Larina I.M. Label-free study of cosmonaut's urinary proteome changes after long-duration spaceflights // Eur. J. Mass. Spectrom (Chichester). 2017 Aug. V. 23(4). P. 225–229. 
15. http://bioinfo.wilmer.jhu.edu/tiger (TiGER) 
16. Gene Ontology Consortium. Gene Ontology annotations and resources // Nucleic Acids Res. 2013 Jan. V. 41(Database issue). P. D530-5. doi: 10.1093/nar/gks1050. Epub 2012 Nov 17.
17. Maere S., Heymans K., Kuiper M. BiNGO: a Cytoscape plugin to assess overrepresentation of gene ontology categories in biological networks // Bioinformatics. 2005 Aug 15. V. 21(16). P. 3448–9. Epub 2005 Jun 21. 
18. Larina I.M., Percy A.J., Juncong Yang, Borchers Ch.H., Nosovsky A.M., Grigoriev A.I., Nikolaev E.N. Protein expression changes caused by spaceflight as measured for 18 Russian cosmonauts // Sci Rep. (Nature Publishing Group). 2017. V. 7. P. 8142. 
19. Brzhozovskiy A., Kononikhin A., Indeykina M., Kashirina D., Popov I., Pastushkova L., Custaud. M.-A., Larina I., Nikolaev E. The effects of space flight factors on the human plasma proteome, including both real space missions and ground-based model experiments // International Journal of Molecular Sciences. 2019. V. 20(13). P. 3194.
20. Butterfield D. A., Perluigi M., Tanea Reed, Tasneem Muharib, Hughes Ch.P., Renã A.S. Robinson, Rukhsana Sultana. Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications // Antioxid Redox Signal. 2012. Dec 1. V. 17(11). P. 1610–1655. 
21. Mahavir Singh, Aniruddh Kapoor, Aruni Bhatnagar Oxidative and reductive metabolism of lipid-peroxidation derived carbonyls // Chem. Biol. Interact. 2015. Jun 5. V. 234. P. 261–273.
22. Semenza Gregg L. Hypoxia-Inducible Factors in Physiology and Medicine // Cell. 2012. Feb 3. V. 148(3). P. 399–408.
23. Kwak Mi-Kyoung, Nobunao Wakabayashi, Greenlaw J.L., Masayuki Yamamoto, Kensler T.W. Antioxidants Enhance Mammalian Proteasome Expression through the Keap1-Nrf2 Signaling Pathway // Mol. Cell. Biol. 2003. Dec. V. 23(23). P. 8786–8794.
24. Hine Ch.M., Mitchell J.R. NRF2 and the Phase II Response in Acute Stress Resistance Induced by Dietary Restriction // J. Clin. Exp. Pathol. Author manuscript; available in J. Clin. Exp. Pathol. 2012. Jun. 19. Suppl 4(4). P. 7329.
25. Dinkova-Kostova A.T., Abramov A.Y. The emerging role of Nrf2 in mitochondrial function // Free Radic. Biol. Med. 2015. Nov. 88(Pt B). P. 179–188. 
26. Deeley R.G., Westlake C., Cole S.P.C. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins // Physiol. Rev. 2006. V. 86. P. 849–899. 
27. Markin A.A., ZHuravleva O.A. Orbital'naya stanciya MIR. Biohimicheskoe issledovanie krovi. Poslepoletnye kliniko-fiziologicheskie issledovaniya. T.1. M.: Anikom. 2001. S. 606 – 612. 
28. Lauder S.N., Allen-Redpath K., Slatter D.A. et al. Networks of enzymatically oxidized membrane lipids support calcium-dependent coagulation factor binding to maintain hemostasis // Sci. Signal. 2017. Nov 28. V. 10(507). P. eaan2787. 
29. Wong W.M., Gerry A.B., Putt W., Roberts J.L., Weinberg R.B., Humphries S.E., Leake D.S., Talmud P.J. Common variants of apolipoprotein A-IV differ in their ability to inhibit low density lipoprotein oxidation // Atherosclerosis. 2007. Jun. V. 192(2). P. 266–74. 
30. Peng J., Li X.P. Apolipoprotein A-IV: A potential therapeutic target for atherosclerosis // Prostaglandins Other Lipid Mediat. 2018. Nov. V. 139.  P. 87–92. 
31. Li X., Xu M., Wang F., Kohan A.B., Haas M.K., Yang Q., Lou D., Obici S., Davidson W.S., Tso P. Apolipoprotein A-IV reduces hepatic gluconeogenesis through nuclear receptor NR1D1 // J. Biol. Chem. 2014. Jan 24. V. 289(4). P. 2396–404. 
32. Altwegg L.A., Neidhart M., Hersberger M., Muller S., Eberli F.R. et al. Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes // Eur Heart J. 2007. V. 28. № 8.  P. 941–948.
33. Cagnin S., Biscuola M., Patuzzo C., Trabetti E., Pasquali A. et al. Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries // BMC genomics. 2009. V. 10. № 1. P. 13. 
34. Croce K., Gao H., Wang Y. et al. Myeloid-related protein-8/14 is critical for the biological response to vascular injury // Circulation. 2009. V. 120. № 5. P. 427–436.
35. Viemann D., Barczyk K., Vogl T. et al. MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program // Blood. 2007. V. 109. № 6. P. 2453–2460. 
36. Crucian B., Sams C. Immune System Dysregulation during Spaceflight : Clinical Risk for Exploration-Class Missions // J. Leukoc. Biol. 2009.  № 86 (November). P. 1017–1018.
37. Kaur I.; Simons E.R., Castro V.A., Mark Ott C., Pierson D.L. Changes in Neutrophil Functions in Astronauts // Brain. Behav. Immun. 2004.  V. 18 (5). P. 443–450.
38. Crucian B., Stowe R., Quiriarte H., Pierson D., Sams C. Monocyte Phenotype and Cytokine Production Profiles Are Dysregulated by Short-Duration Spaceflight // Aviat. Sp. Environ. Med. 2011. V. 82 (9). P. 857–862.
39. Indo H.P., Majima H.J., Terada M., Suenaga S., Tomita K., Yamada S., Higashibata A., Ishioka N., Kanekura T., Nonaka I. et al. Changes in mitochondrial homeostasis and redox status in astronauts following long stays in space // Sci. Rep. 2016. V. 6. doi: 10.1038/srep39015.
40. Anselm V., Novikova S., Zgoda V. Re-Adaption on Earth after Spaceflights Affects the Mouse Liver Proteome // Int. J. Mol. Sci. 2017. V. 18.  P. 1763. 
41. Blaber E.A., Pecaut M.J., Jonscher K.R. Spaceflight Activates Autophagy Programs and the Proteasome in Mouse Liver // Int. J. Mol. Sci. 2017.  V. 18. P. 2062.